The present invention relates to processes for the preparation of trifluorophenylacetic acids useful as intermediates in the preparation of certain inhibitors of the dipeptidyl peptidase-IV (“DP-IV” or “DPP-IV”) enzyme, drugs that are useful in the treatment of diabetes, and particularly type 2 diabetes. See, e.g., WO 97/40832, WO 98/19998, U.S. Pat. No. 5,939,560, Bioorg. Med. Chem. Lett., 6, 1163-1166 (1996); and Bioorg. Med. Chem. Lett., 6, 2745-2748 (1996).
Similar syntheses of phenylacetic acid derivatives from aryl halides with varying substituents have been described, e.g., in Shi, et al., Tetrahedon, 55, 908-918 (1999); U.S. Pat. No. 6,395,921; Lindley, J., Tetrahedron, 40, 1433-1456 (1984); and Setsune, et al., Chem. Ltrs., 367-370, (1981). These references describe the preparation of [bis-(trifluoromethyl)-phenyl]-acetic acids, but are not amenable to scale-up and preparation of multi-kilogram quantities. The present invention provides an effective two-step method for preparing trifluorophenylacetic acids quickly and efficiently.
In accordance with the present invention, a trifluorphenyl-Grignard reagent, i.e., magnesium-trifluorobenzene, produced from the contact of bromo-trifluorobenzene with magnesium chloride, is reacted with an allylating agent, such as allyl bromide, to form an olefin, i.e. 1-(2-propenyl)-2,4,5-trifluorobenzene, which is then oxidatively cleaved to produce the requisite trifluorophenylacetic acid. Purity and yields seen with the present process are unexpectedly high, and the two step procedure allows rapid, cost efficient and large-scale synthesis.